AD: Neuropathology

Question 1

Key neuropathological features in AD?

Answer 1

• extracellular Aβ plaques within brain parenchyma
• neurofibrillary tangles (NFTs)
• cerebral amyloid angiopathy (Aβ deposition in blood vessel)
• neuronal loss (cerebral atrophy)

Question 2

Extracellular Aβ plaques (“senile”/”neuritic” plaques) forms?

Answer 2

Classical (neuritic) or diffuse

Question 3

Dustbin hypothesis of extracellular Aβ plaques?

Answer 3

Cells expel Aβ (as too much intracellularly) -> accumulates in EC space -> glial reaction

Question 4

NFTs correlation w/ dementia?

Answer 4

Best correlation w/ dementia (used to grade pathology)

Question 5

NFTs composition and forms

Answer 5

Contains paired helical filaments

Found as NFT or neuropil threads (dendrites)

Question 6

How to stain for NFTs?

Answer 6

Use antibody against hyperphosphorylated Tau or silver staining

Question 7

Describe the cholinergic hypothesis

Answer 7

Increased age -> decreased ACh turnover

[AD is characterised by cerebral cholinergic denervation]

Question 8

Cholinergic hypothesis relationship w/ cognition?

Answer 8

Cholinergic defects underlie memory loss and related cognitive problems

Decreased cholinergic markers correlate w/ dementia severity

Question 9

Variants of treatment using cholinergic hypothesis (+ effectiveness)?

Answer 9

Lessathine : ineffective as precursor can’t reach pre-synaptic terminal

Ligand: minimally effective

AChEi: main treatment]- mild benefits in early AD but doesn’t prevent progression

Question 10

Currently available AD treatments?

Answer 10

• Anticholinesterases: donepezil, tacrine, rivastigmine
• nACh receptors (increases stimulation): galantamine
• Glutamate antag: memantine]- may also be useful in vasc. dementia

Question 11

Describe the amyloid cascade hypothesis

Answer 11

Any factor that alters AP metabolism to favour Aβ production could favour AD

Altered APP metab -> Aβ deposition -> neuritic Aβ plaques -> NFTs and neuronal damage -> dementia

Question 12

Provide an overview of Braak’s staging

Answer 12

[for Tau, which correlates w/ AD progression better than tau]

1. transenterohinal region, medial temporal lobe
   2, extends to enterohinal region, posterior hippocampus
2. adjacent entorhinal cortex
3. rest of temporal cortex
4. occipital cortex (visual association areas)
5. occiptal cortex (primary visual cortex)

Question 13

At what stages of Braak’s staging, do cognitive symptoms appear?

Answer 13

Between 3 and 4

Question 14

What is APP and its composition?

Answer 14

Membrane bound glycoprotein (carboxy intracellular, NH2 extracellular, beta-amyloid in membrane region)

Question 15

Where is APP found in the body?

Answer 15

In all cells

Question 16

What is non-amyloidogenic cleavage?

Answer 16

alpha-secretase cuts within Aβ sequence]- main physiological pathway, non-pathological

Question 17

What is amyloidogenic cleavage?

Answer 17

beta-secretase and gamme-secretase to release intact Aβ]- pathological protein

Question 18

Outcome Aβ accumulation intracellularly?

Answer 18

Intracellular Aβ -> Ca2+ dysfunction -> mitoch. and proteasome inhibition -> ROS

[extracellular plaque is a “dustbin”]

Question 19

Risk factors for AD?

Answer 19

• age
• FHx
• Down’s syndrome
• Previous head trauma
• PD
• depression

Question 20

Describe the mutations in Familial AD?

Answer 20

APP mutation: codon 717 (point mutation val-> lle)]- london mutation

Presenilin 1/2: role in intracellular signalling]- accounts for most familial AD; presenilin has gamma-secretase

Question 21

AD risk genes?

Answer 21

• ApoE4: role in lipid metab
• TREM2: heterozyhous variant
• GWAS SNPs: modify risk e.g. Apoe4

Question 22

ApoE4 significance?

Answer 22

[role in lipid metabolism on Chr19]

50% of AD have E4 allele

E4 homozyogte -> 10x greater risk

Associated w/ late onset AD

Question 23

Relationship between head injury and AD?

Answer 23

• acute head injury associated w/ AD-like changes “dementia pugilistica” aka CTE]- if survived, would they develop AD?

30% of head injury develop Aβ deposits withing weeks (these ppl have high ApoE4 incidence)

Question 24

Mechanism relating head injury and AD?

Answer 24

Cytokine cycle:

Microglial activation -> normally resolves but +ve feedback -> neuroinflammation (IL-1,ApoE4) -> neurodegenerative

Question 25

Post Mortem Examination Findings:

Overview of therapeutic approaches for AD?

Answer 25

• stop Aβ aggregation]- if plaques are dustbin, this causes increased intracell accumulation
• clear Aβ plaques
• reduce Aβ expression]- but APP is a normal physiological protein
• alter Aβ expression (enhance a-secretase, inhibit b/g-secretase)
• anti-inflammatories (assoc. between NSAID use and low AD risk)
• tissue transplants

Question 26

Animal studies for clearing Aβ plaques?

Answer 26

Vaccination -> antibodies against Aβ -> clear brain pathology

Autopsy case report showed Aβ cleared but no change in disease course]- but 25% didnt have AD

human studies stopped due to meningioencephalitis

Question 27

Significance of Chr21 in AD?

Answer 27

Variety of point mutations: London mut, Swedish mut, Arctic, HCHWA-D

All these mutations are at the secretase sites- sites that will increase beta-amyloid

Question 28

Significance of presinilin in AD?

Answer 28

Part of the gamma-secretase complex